Abstract
Over the last three decades, V-ATPases have emerged from the obscurity of poorly understood membrane proton transport phenomena to being recognized as ubiquitous proton pumps that underlie vital cellular processes in all eukaryotic and many prokaryotic cells. These exquisitely complex molecular motors also engage in diverse specialized roles contributing to development, tissue function and pH homeostasis within complex organisms. Increasingly, mutations and misappropriation of V-ATPase function have been linked to diseases, ranging from sclerosing bone pathologies and renal tubular acidosis to bone-loss disorders and cancer metastasis. Much remains to be learned about the details of V-ATPase cell and molecular biology; nevertheless, interest in V-ATPases as potential therapeutic targets has burgeoned in recent years. In this review, we present a history of our involvement and contributions to the understanding of V-ATPase structure and function and our nascent and ongoing contributions to translating the knowledge gained from basic research on the nature of V-ATPases into tools for drug discovery. We focus here primarily on the treatment of bone-loss pathologies, like osteoporosis, and present proof-of-concept for a drug screening strategy based on targeting a3-B2 subunit interactions within the V-ATPase complex.
Keywords: Bone loss pathology, drug discovery, high throughput screening, membrane transport, osteolysis, osteoporosis, protein interaction, tumor metastasis, vacuolar proton-translocating ATPase, vesicular proton pump, V-type H+-ATPase
Current Protein & Peptide Science
Title:V-ATPase Subunit Interactions: The Long Road to Therapeutic Targeting
Volume: 13 Issue: 2
Author(s): Norbert Kartner and Morris F. Manolson
Affiliation:
Keywords: Bone loss pathology, drug discovery, high throughput screening, membrane transport, osteolysis, osteoporosis, protein interaction, tumor metastasis, vacuolar proton-translocating ATPase, vesicular proton pump, V-type H+-ATPase
Abstract: Over the last three decades, V-ATPases have emerged from the obscurity of poorly understood membrane proton transport phenomena to being recognized as ubiquitous proton pumps that underlie vital cellular processes in all eukaryotic and many prokaryotic cells. These exquisitely complex molecular motors also engage in diverse specialized roles contributing to development, tissue function and pH homeostasis within complex organisms. Increasingly, mutations and misappropriation of V-ATPase function have been linked to diseases, ranging from sclerosing bone pathologies and renal tubular acidosis to bone-loss disorders and cancer metastasis. Much remains to be learned about the details of V-ATPase cell and molecular biology; nevertheless, interest in V-ATPases as potential therapeutic targets has burgeoned in recent years. In this review, we present a history of our involvement and contributions to the understanding of V-ATPase structure and function and our nascent and ongoing contributions to translating the knowledge gained from basic research on the nature of V-ATPases into tools for drug discovery. We focus here primarily on the treatment of bone-loss pathologies, like osteoporosis, and present proof-of-concept for a drug screening strategy based on targeting a3-B2 subunit interactions within the V-ATPase complex.
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Cite this article as:
Kartner Norbert and F. Manolson Morris, V-ATPase Subunit Interactions: The Long Road to Therapeutic Targeting, Current Protein & Peptide Science 2012; 13 (2) . https://dx.doi.org/10.2174/138920312800493179
DOI https://dx.doi.org/10.2174/138920312800493179 |
Print ISSN 1389-2037 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5550 |
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